1. Technical Field
This document relates to methods and materials involved in apoptosis, apoptosis inhibitors, and to modulating the activity of TRAIL.
2. Background Information
Apoptosis is a normal physiologic process leading to cell death that can be induced by normal processes as well as several pathological conditions and injuries. Apoptosis can be involved in conditions including, but not limited to, cardiovascular disease, cancer, immunoregulation, viral diseases (e.g., HIV infection), anemia, neurological disorders, gastrointestinal disorders, diabetes, hair loss, rejection of organ transplants, prostate hypertrophy, obesity, ocular disorders, stress, and aging.
TNF related apoptosis inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) superfamily of death-inducing ligands whose members include Fas ligand and TNF. Ligation of TRAIL to its cognate receptors can cause cell death by apoptosis or may cause NF-κB activation (Hu, et al., J. Biol. Chem., 274:30603-10 (1999)). There are three known TRAIL isoforms (TRAILα, TRAILβ, and TRAILγ). TRAIL has widespread expression on multiple cell lineages and has shown potent toxicity for many tumors and virally infected cells, while sparing most healthy cells (Held, et al., Drug Resist. Updat., 4:243-52 (2001); Baetu and Hiscott, Cytokine Growth Factor, 13:199-207 (2002)). TRAIL mediates cell death via binding of one of five TRAIL receptors (e.g., TRAIL-R1, -R2, -R3, -R4, and osteoprotegerin (OPG)). TRAIL-R1 and -R2 can cause an apoptotic signal, while TRAIL-R3 and -R4 lack intracellular regions that can propagate an apoptotic signal (Wang and El-Deiry, Oncogene, 22:8628-33 (2003)).
OPG, a soluble inhibitor of RANK ligand, also binds to TRAIL in humans, and can be a soluble decoy receptor for TRAIL (Emery, et al., J. Biol. Chem., 273:14363-7 (1998); Holen, et al., Cancer Res., 62:1619-23 (2002)). Expression of TRAIL-R1, TRAIL-R2, or TRAIL-R1 and TRAIL-R2 on a cell is required to induce TRAIL-mediated apoptosis of that cell. However, TRAIL-R1 and/or -R2 receptor expression alone is insufficient to render a cell susceptible to TRAIL-mediated cell death. TRAIL agonists are in pre-clinical development for used as therapy for human tumors because of their selective induction of cell death in transformed and virally infected cells.